Despite decades of research, affective disorders are prevalent and associated with significant morbidity and mortality. Unraveling the pathophysiology of affective disorders has been uniquely challenging because depressive syndromes are heterogeneous and have diverse etiologies. We propose to address this problem by studying perimenopausal major depressive disorder (MDD), a more homogeneous depression subtype with an established trigger (i.e., estradiol withdrawal). Focusing on perimenopausal MDD will therefore increase the likelihood of identifying meaningful neurobiological markers. One of the most powerful tools for understanding the neurobiological mediators of MDD is brain imaging. Prior research suggests that the frontostriatal reward system is regulated by estradiol and implicated in MDD. However, the neural pathophysiology of perimenopausal MDD has never been studied. We will use functional magnetic resonance imaging (fMRI) at baseline and following estradiol treatment to 1) measure the frontostriatal response to reward in perimenopausal MDD and test the effects of estradiol on neural activation in perimenopausal women; 2) quantify behavioral responses to reward at baseline and following estradiol administration in perimenopausal women with and without MDD; and 3) measure the psychological correlates of the frontostriatal response to reward in women with perimenopausal MDD at baseline and following estradiol administration. This study design will allow us to explore the neural pathophysiology of perimenopausal MDD, the effects of estradiol on the neural reward system, and the degree to which neural reward system dysfunction predicts the antidepressant effects of estradiol. This research will support my primary career goal to become an independently funded clinical scientist with the expertise necessary to conduct state-of-the-art mechanistic research on the neuroendocrinology of reproductive mood disorders. My long-term research objectives are to 1) advance our understanding of the effects of ovarian hormones on the brain and how these effects contribute to the triggering of and susceptibility to reproductive-related mood disorders; and 2) to identify neural and endocrine markers of depression risk, thereby improving our ability to prevent affective illness in women. The training and research plan outlined in this proposal are designed to supplement my previous experience with a novel, clinically relevant program of research at the intersection of behavioral endocrinology and neuroscience. The specific objectives to meet my career goal are to 1) obtain focused training in neuroscience and fMRI data acquisition and analysis; 2) develop expertise in neuroendocrinology and hormone administration; 3) gain experience with conducting clinical research in perimenopausal women; and 4) obtain expertise and pilot data to support an interdisciplinary research program principally funded by NIH R01 grants. This career development application represents the critical next step in my academic and research training. Although the ultimate measure of successful training will be the attainment of independent funding by the end of the award period, benchmarks that will be used to determine progress toward my training and research goals include participant enrollment, creation of a data analysis pipeline, manuscript preparation, conference presentations, and grant writing. The proposed training and research activities will prepare me to lead an independently funded research program focused on the neuroendocrine pathophysiology of reproductive mood disorders. In addition to supporting my career development objectives, the proposed research represents the first step in characterizing neural mechanisms of reproductive hormone-related affective dysfunction during the perimenopausal period. The impact of this research is expected to be an improved understanding of the neuroendocrine pathophysiology of perimenopausal MDD. Future directions for this work will include identifying neural biomarkers that predict reproductiv mood disorder susceptibility and response to hormonal interventions, and exploring neuroendocrine etiological pathways that may help to explain the preponderance of depression in women.